Alpha‐Synuclein

Abstract

α‐Synuclein (αS) is a presynaptic small protein that has attracted much interest because its aggregation and accumulation
in the form of amyloid fibrils is the hallmark of a range of neurodegenerative disorders, collectively referred to as synucleinopathies.
Despite intense research on this protein since it was first identified two decades ago as the major component of the proteinaceous
intracellular inclusion characteristics of Parkinson disease, there is still no consensus on the physiological function of
the protein and much remains to be established on the molecular basis of its toxicity. Recently, important steps have been
undertaken to identify the different conformational states that this protein is able to adopt and elucidate their role in
physiological and pathological conditions.

Key Concepts

The physiological function(s) of α‐synuclein remains controversial, although recent evidences suggest a major regulatory role
in synapsis.

At physiological conditions, α‐synuclein is in a dynamic equilibrium between a membrane‐bound α‐helical (likely multimeric)
conformation and a cytosolic intrinsically disordered (monomeric) conformation.

α‐Synuclein aggregation and fibril formation likely play a central role in Parkinson disease and other neurodegenerative disorders.

Different strains or fibril polymorphs of α‐synuclein have different degrees of infectivity and might be associated with distinct
types of pathologies.

Different mechanisms of formation of α‐synuclein amyloid aggregates have been observed in vitro, but their relative relevance in vivo remains unknown.

Recent studies support the idea that multiple aggregated species of α‐synuclein can be generated through diverse misfolding
pathways during the process of amyloid aggregation and could play distinct roles during the development of disease.

Figure 2.Mechanisms of formation of amyloid aggregates. There are generally two main processes that generate new aggregates: primary nucleation processes, where new aggregates form
at a rate dependent only on the concentration of monomeric species, and secondary processes, where the new aggregates are
formed at a rate dependent on the concentration of existing fibrils, being fibril fragmentation and secondary nucleation the
most relevant secondary processes (Cohen et al.,). An additional mechanism typically involved in the processes of fibril formation, but that does not generate new aggregates
per se is fibril elongation (that is typically associated with ‘fibril seeding’). The formation of oligomeric species in αS
(highlighted with red circles) has been reported in primary nucleation processes (Cremades et al.,) and might also occur in fibril surface‐catalysed secondary nucleation processes as recently described for Aβ42 (Cohen et al.,). The primary nucleation of αS has been suggested to follow a nucleation‐conversion‐polymerisation mechanism, where αS monomeric
molecules assemble initially into primarily disordered oligomers that slowly convert into more stable, β‐sheet oligomers that
ultimately convert into amyloid fibrils by further growth and rearrangement (Cremades et al.,; Iljina et al.,).

Figure 4.Representation of a putative energy surface for the amyloid aggregation process. The energy landscape for the formation of amyloid aggregates is likely to be rugged and to be characterised by large numbers
of degenerate energy states with significant energy barriers between different regions of the conformational space. The consequence
of such a landscape is the existence of multiple pathways with multiple oligomeric species. Some pathways will generate oligomeric
species that are only transient and that rapidly elongate and convert into fibrils (e.g. the pathway depicted in yellow),
but other pathways will generate oligomeric species that are trapped in local minima and, therefore, accumulate (e.g. the
pathway depicted in red). These oligomers present a structural configuration that is not optimal for elongation and therefore
could only transform into fibrils after major structural rearrangements that are likely to be slow (dashed red arrows). Reproduced from Cremades and Dobson (2017) Elsevier.

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